In recent decades, basic and clinical investigation has helped to elucidate the multifactorial and multidimensional differences between women and men with acute coronary syndrome (ACS).1 Emerging interest in coronary heart disease in women has revealed sex differences in pathophysiology and clinical presentation, preventive interventions and diagnostic strategies, and ACS management and therapeutic responses.2 Despite these differences, the literature supports equal benefit from evidence-based treatment of ACS for women and men and the need to promote and implement stringent guidelines for the management of ACS in women.3

Comparisons of sex differences in the quality of care for ACS pose challenges due to the multiple dimensions within the care process.4 Based on European Society of Cardiology (ESC) guidelines for the management of ACS, the ESC Acute Cardiovascular Care Association (ACCA) proposed a set of quality indicators (QIs) for the management of acute myocardial infarction (AMI).4 This set comprises 20 QIs across 7 domains and includes evaluation of the key aspects within the AMI care pathway. These indicators were recently validated using data from the National Health Service of England and Wales (Myocardial Ischaemia National Audit Project) and showed their potential to improve care and reduce unwarranted variation in death from AMI.5 The indicators may also be a useful tool to study sex inequalities in the process of care and outcomes of ACS in current settings. Through a prospective cohort study, we assessed differences by sex in quality of care and 30-day mortality using the ESC ACCA QIs for AMI.

As determined using the EPIHeart prospective cohort study, 6 of the 7 ESC ACCA QI domains for AMI showed worse performance for women than for men. Fewer women than men received timely reperfusion, were discharged on dual antiplatelet therapy and high-intensity statins, and were referred for cardiac rehabilitation. They also scored lower in the main composite QI for advisable interventions. An inverse association between the attainment of composite QI and mortality was observed for both sexes. Without differences by sex, we found low levels of ischemic and bleeding risk stratification assessment using the GRACE and CRUSADE prognostic tools and use of fondaparinux in eligible NSTEMI patients.

The ACS care pathway is complex and difficult to evaluate. Patient and system factors have competing effects on patient flow through the health care system. These factors often influence each other and act at different times during an episode of illness and care.17 Disparities in health care and outcomes between women and men are multifactorial and occur at different levels of the ACS process of care pathway.18,19 The differences in demographic, socioeconomic, and cardiovascular risk factors, comorbidities, and presentation severity between women and men in our cohort are in line with recent data focused on the multifactorial determinants of sex disparities in coronary heart disease management and outcomes.2

The QI results for the reperfusion/invasive strategy strengthen the importance of timeliness of health care delivery in the provision of care. Time-based QIs are significantly influenced by hospital system factors adjusted for patient factors, namely patient delay times.20 In fact, the high level of reperfusion distracts attention from the low level of timely reperfusion for both sexes–which is even significantly lower for women–and for patients admitted to both PCI- and non-PCI-capable hospitals. The very low proportion of patients, particularly women, transferred from non-PCI-capable hospitals for primary PCI within the target 30-minute door-in door-out time is particularly relevant in terms of health policy and planning. According to the Codi Infart registry of Catalonia, a first medical contact to arterial access time exceeding 120 minutes is strongly associated with initial admittance of a patient to a center without a catheterization laboratory.21 Implementation of the national coronary fast-track system in Portugal largely contributed to a 2-fold increase in primary angioplasty incidence from 2010 to 2015,22 but there are no data on the parallel achievement and improvement of timely reperfusion. Because these networks favor primary angioplasty rather than thrombolysis, their implementation might result in time delays that outweigh the benefits of mechanical reperfusion.21 The difference between the proportions of women and men undergoing coronary angiography within 72hours of admission is not significant, which may indicate an improvement in the timeliness of this invasive strategy for NSTEMI patients. Among patients with NSTEMI, the indication for an invasive approach depends on numerous patient factors.3 Factors possibly influencing this indication include frailty, poor cognitive status, and other comorbidities. In addition, estimated life expectancy decreases with age, and women in our cohort were significantly older than men. Not all of these factors were considered in the QI assessment. However, the main NSTEMI QI for an invasive strategy is a time-based indicator that measures time delays and not the decision to proceed with an invasive approach.

The very low level of performance of the GRACE and CRUSADE assessments among both women and men should be addressed because objective risk assessment using risk scores provides superior risk discrimination when compared with physician estimated risk.23

Use of incomplete drug combinations after an ACS is associated with a higher risk of cardiovascular morbidity and all-cause mortality.24 Results from a retrospective cohort study revealed that in Portugal women with STEMI were less likely to be discharged on aspirin and clopidogrel.25 These results are in line with our findings that a lower proportion of eligible women were discharged on dual antiplatelet therapy. High-intensity statins are recommended in all patients with AMI, irrespective of the cholesterol concentration at presentation.26 Previous studies reporting on the very high number of statin prescriptions for secondary prevention after an ACS among women and men did not address the specific types of statins.5,25 However, inadequate adherence to recommendations for high-intensity statins has already been reported27 and our results from the EPIHeart study amplify preexisting knowledge on sex differences in these prescription practices. The use of lower-intensity statin therapy may be considered in patients with an increased risk of adverse effects from statins (ie, elderly patients and those with hepatic or renal impairment, previous adverse effects, or a potential interaction with another essential concomitant therapy).26 In actual practice, frail patients who also have very low baseline low-density lipoprotein cholesterol are more likely to be discharged on lower-intensity statin therapy. However, no information was available in this study on the low-density lipoprotein cholesterol levels at presentation or the patient subgroup with an increased risk of adverse effects from statins. There were no observed differences by sex for antithrombotics and secondary prevention discharge treatment, with high levels of performance for all treatments, except for anticoagulation therapy with fondaparinux. Treatment with fondaparinux was also the QI with the widest hospital variation in the Myocardial Ischaemia National Audit Project registry.5 Although not all drug class-relative contraindications were taken into account, the most relevant variables were considered to achieve our objectives.

Increased referral to cardiac rehabilitation after an ACS, especially among women, can further reduce differences in mortality by sex because cardiac rehabilitation referral and attendance is associated with a more significant reduction in mortality in women than in men.28 The higher rates of smoking cessation advice observed for eligible women vs men may be due to evidence that this guidance is more appropriate for women because female smokers have a greater risk of developing cardiovascular disease than male smokers.1

After adjustment for GRACE score, women had twice the 30-day mortality rate of men. However, factors not captured by the GRACE risk score may have had an impact on outcomes, such as frailty and patient adherence to secondary prevention. These omissions likely limit definitive conclusions on the association between sex and the 30-day mortality rate.29,30

Due to the small number of deaths in our cohort, along with the difficulty in demonstrating the association between a single QI and the clinical outcome,31 the composite QI was used to measure the relationship between process and outcome indicators. An inverse association was found between crude mortality and attainment of this QI covering the spectrum of the AMI care pathway. However, this finding must be considered with caution because the small number of deaths, within the tertiles of attainment of the composite QI, precluded adjustment for possible confounders. Adherence to the recommended guidelines for management and treatment performance indicators has already been associated with outcomes for patients with AMI.32,33 Our results are in line with findings that sex-related differences have not been eliminated, although more than a decade has passed since sex disparities in management and outcomes were first described in a large-scale observational study.34–36 Additional in-depth studies are needed to explain our findings, particularly to explore the causal pathways for the associations between sex management and outcomes in ACS patients.

The QIs state the required explicit diagnostic or therapeutic actions, as well as define how to identify patients needing a specific action. A unique and universal standardized set of QIs for ACS does not exist. In 2015, the Spanish Society of Cardiology and the Spanish Society of Thoracic and Cardiovascular Surgery organized a task force to define outcome and process indicators for hospital cardiology practice.37 Measurement and reporting of variations by sex using validated QIs has the potential to further reduce sex inequalities in quality of care, with the ultimate goal of decreasing the higher 30-day mortality for women with AMI.

Applying the ESC ACCA QIs, we found differences in quality of care at different levels of the care pathway between women and men with AMI. These findings, along with the association of the composite QI with 30-day mortality, which is still higher in women (and although we cannot conclude that this difference in outcome is explained by sex per se) provide evidence to support measuring these validated QIs separately by sex, so as to improve guideline recommendations for management and reduce mortality from AMI in women.

This work was supported by FEDER through the Operational Programme Competitiveness and Internationalization and national funding from the Foundation for Science and Technology – FCT (Portuguese Ministry of Science, Technology and Higher Education) (FCOMP-01-0124-FEDER-028709), under the project “Inequalities in coronary heart disease management and outcomes in Portugal” (Ref. FCT PTDC/DTP-EPI/0434/2012) and Unidade de Investigação em Epidemiologia - Instituto de Saúde Pública da Universidade do Porto (EPIUnit) (POCI-01-0145-FEDER-006862; Ref. UID/DTP/04750/2013).

None declared.